chr3-141487100-C-T

Position:

• chr3-141487100-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006506.5(RASA2):​c.17C>T​(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,392,716 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (25 hom.)
• Consequence: RASA2 NM_006506.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.315

Genes affected

RASA2 (HGNC:9872): (RAS p21 protein activator 2) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004214376).
• BP6: Variant 3-141487100-C-T is Benign according to our data. Variant chr3-141487100-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218684.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA2	NM_006506.5	c.17C>T	p.Pro6Leu	missense_variant	1/24	ENST00000286364.9
RASA2	NM_001303246.3	c.17C>T	p.Pro6Leu	missense_variant	1/25
RASA2	NM_001303245.3	c.17C>T	p.Pro6Leu	missense_variant	1/24
RASA2	XM_047448652.1	c.17C>T	p.Pro6Leu	missense_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA2	ENST00000286364.9	c.17C>T	p.Pro6Leu	missense_variant	1/24	1	NM_006506.5	P1
RASA2	ENST00000515549.1	c.17C>T	p.Pro6Leu	missense_variant, NMD_transcript_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 509 AN: 150574 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00231

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000805

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00290

GnomAD3 exomes AF: 0.00357 AC: 281 AN: 78770 Hom.: 2 AF XY: 0.00317 AC XY: 141 AN XY: 44512

Gnomad AFR exome AF: 0.000897

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.000191

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00132

Gnomad FIN exome AF: 0.000727

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00545 AC: 6773 AN: 1242034 Hom.: 25 Cov.: 31 AF XY: 0.00532 AC XY: 3252 AN XY: 611394

Gnomad4 AFR exome AF: 0.000716

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.000105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00634

Gnomad4 OTH exome AF: 0.00503

GnomAD4 genome AF: 0.00337 AC: 508 AN: 150682 Hom.: 1 Cov.: 32 AF XY: 0.00293 AC XY: 216 AN XY: 73610

Gnomad4 AFR AF: 0.000918

Gnomad4 AMR AF: 0.00231

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000805

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.00322

ESP6500AA AF: 0.000741 AC: 2

ESP6500EA AF: 0.00223 AC: 13

ExAC AF: 0.00152 AC: 149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	RASA2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: RASA2 c.17C>T (p.Pro6Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 78770 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 713 fold of the estimated maximal expected allele frequency for a pathogenic variant in RASA2 causing Noonan Syndrome and Related Conditions phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.17C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

RASA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.97
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.88	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.11
Sift	Benign	0.18	T;T
Sift4G	Benign	0.24	T;T
Vest4		0.10
MVP		0.74
MPC		0.35
ClinPred		0.047	T
GERP RS		1.6
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201352230; hg19: chr3-141205942;